Circulating acylcarnitines as biomarkers of mitochondrial dysfunction after acetaminophen overdose in mice and humans

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• 作者：Mitchell R. McGill (1)
  Feng Li (1)
  Matthew R. Sharpe (2)
  C. David Williams (1)
  Steven C. Curry (3) (4)
  Xiaochao Ma (1)
  Hartmut Jaeschke (1)
  
• 关键词：Acetaminophen toxicity ; Biomarkers ; Mitochondria ; Acylcarnitines
• 刊名：Archives of Toxicology
• 出版年：2014
• 出版时间：February 2014
• 年：2014
• 卷：88
• 期：2
• 页码：391-401
• 全文大小：1,047 KB
• 作者单位：Mitchell R. McGill (1)
  Feng Li (1)
  Matthew R. Sharpe (2)
  C. David Williams (1)
  Steven C. Curry (3) (4)
  Xiaochao Ma (1)
  Hartmut Jaeschke (1)
  
  1. Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, KS, 66160, USA
  2. Department of Internal Medicine, University of Kansas Hospital, Kansas City, KS, USA
  3. Department of Medical Toxicology, Banner Good Samaritan Medical Center, Phoenix, AZ, USA
  4. Department of Medicine, Center for Toxicology and Pharmacology Education and Research, University of Arizona College of Medicine, Phoenix, AZ, USA
  
• ISSN：1432-0738

文摘

Acetaminophen (APAP) is a widely used analgesic. However, APAP overdose is hepatotoxic and is the primary cause of acute liver failure in the developed world. The mechanism of APAP-induced liver injury begins with protein binding and involves mitochondrial dysfunction and oxidative stress. Recent efforts to discover blood biomarkers of mitochondrial damage have identified increased plasma glutamate dehydrogenase activity and mitochondrial DNA concentration in APAP overdose patients. However, a problem with these markers is that they are too large to be released from cells without cell death or loss of membrane integrity. Metabolomic studies are more likely to reveal biomarkers that are useful at early time points, before injury begins. Similar to earlier work, our metabolomic studies revealed that acylcarnitines are elevated in serum from mice after treatment with toxic doses of APAP. Importantly, a comparison with furosemide demonstrated that increased serum acylcarnitines are specific for mitochondrial dysfunction. However, when we measured these compounds in plasma from humans with liver injury after APAP overdose, we could not detect any significant differences from control groups. Further experiments with mice showed that N-acetylcysteine, the antidote for APAP overdose in humans, can reduce acylcarnitine levels in serum. Altogether, our data do not support the clinical measurement of acylcarnitines in blood after APAP overdose due to the standard N-acetylcysteine treatment in patients, but strongly suggest that acylcarnitines would be useful mechanistic biomarkers in other forms of liver injury involving mitochondrial dysfunction.